Antibacterial agents: soluble salts and aqueous formulations of pyronins

Abstract

The invention provides salts of formula Ia, Ib, Ic, or Id: wherein variables are as described in the specification, as well as compositions comprising a salt of formula Ia-Id, methods of making such salts, and methods of using such salts as, e.g., inhibitors of bacterial RNA polymerase and as antibacterial agents.

What is claimed is: 
     
       1. A composition comprising the salt of formula Ia: 
       
         
           
           
               
               
           
         
         wherein: 
         W is sulfur oxygen, or nitrogen; 
         X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon; 
         one of R 1  and R 2  is C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 1 -C 10  alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 1 -C 10  alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5  alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5  alkyl, C 1 -C 5  alkoxy, aryl, or heteroaryl, wherein any C 1 -C 5  alkyl, C 1 -C 5  alkoxy, aryl, and heteroaryl is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5  alkyl, or C 1 -C 5  alkoxy; or one of R 1  and R 2  is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 1 -C 10  alkoxy; and the other of R 1  and R 2  is absent or is one of H, halogen, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 1 -C 10  alkoxy, wherein any C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 1 -C 10  alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5  alkoxy; 
         R 3  is absent, or is one of H, C 1 -C 2  alkyl, or halogen-substituted C 1 -C 2  alkyl; 
         R 4  is absent, or is one of H, halogen, C 1 -C 2  alkyl, or halogen-substituted C 1 -C 2  alkyl; 
         R 6  is H, halogen, or methyl that is optionally is substituted by halogen; 
         G is one of —CH═CH—NHC (O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC (O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 ; 
         R 7  is one of C 1 -C 6  alkyl, —O (C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), or —N(R 8 ) 2 , provided R 7  is not deuterated alkyl; 
         each R 8  is independently one of hydrogen or —C 1 -C 6  alkyl; 
         R 9  is C 1 -C 10  alkyl or C 2 -C 10  alkenyl, wherein any C 1 -C 10  alkyl or C 2 -C 10  alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ; 
         each R a  is C 1 -C 10  alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5  alkoxy; 
         each R b  is H or C 1 -C 10  alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5  alkoxy; and 
         M +  is a pharmaceutically acceptable cation; and water, wherein the composition is substantially co-solvent free, substantially surfactant free, and has a pH of from about 7 to about 9, and wherein the concentration of the salt is at least about 0.25 mg/mL. 
       
     
     
       2. The salt: 
       
         
           
           
               
               
           
         
       
     
     
       3. A composition comprising the salt of  claim 2  and water, wherein the composition is substantially co-solvent free, substantially surfactant free, and has a pH of from about 7 to about 9, and wherein the concentration of the salt is at least about 0.25 mg/mL.